Method for preparing aminoalkanol esters of 3-methylflavone-8-carboxylic acid

ABSTRACT

3-PROPIONYLSALICYLIC ACID IS MADE BY ISOMERISING 2-HYDROXY-3ALLYLPROPIOPHENONE TO 2-HYDROXY-3-PROPENYLPROPIOPHENONE, OXIDIZING THE LATTER TO 3-PROPIONYLSALICYLIC ALDEHYDE AND OXIDIZING THE LATTER TO 3-PROPIONYLSALICYLIC ACID. This product can be converted to lower alkyl esters which can be used for the production of 3-methylflavone-8-carboxylic acid and its esters, particularly the aminoalkyl esters which are therapeutically active.

United States Patent Sianesi [45] July 1, 1975 [54] METHOD FOR PREPARING 3,350,411 10/1967 Da Re 260/3452 AMINOALKANOL ESTERS OF 3,450,717 6/1969 Kramer et al 260/3405 3 METHYLFLAVONE S CARBOXYLIC 3,637,718 1/1972 Kramer et a1. 260/2955 B ACID [75] Inventor: Enrico Sianesi, Milan, Italy i y minrG- ThOmaS Todd Attorney, Agent, or FirmStevens, Davis, Miller & [73] Ass1gnee. Recordatl SA, Lugano, Switzerland M osher [22] Filed: Apr. 4, 1972 [21] Appl. No: 241,094

Related us. Application Data [571 ABSTRACT [62] gg g g 90916 1970 3-propionylsalicylic acid is made by isomerising 2- hydr0xy-3-allylpropiophenone to 2-hydroxy-3- [30] Foreign Application Priority Data propenylpropiophenone, oxidizing the latter to 3-propionylsalicylic aldehyde and oxidizing the latter to Aug. 1, 1970 Italy 28190/70 p p y y acid. This product can be verted to lower alkyl esters which can be used for the 260/29358; 260/2472 production of 3-methylflav0ne-S-carboxylic acid and I o a s s s [58] Field of Search 260/293.58, 247.2 B, 345.2 therapeutically active [56] References Cited UNITED STATES PATENTS 1/1960 Da Re 260/2472 4 Claims, No Drawings METHOD FOR PREPARING AMINOALKANOL ESTERS OF 3-METHYLFLAVONE-8-CARBOXYLIC ACID This is a division of application Ser. No. 90,016, filed 11-16-70 now US. Pat. No. 3,770,802.

This invention relates to a method for preparing a new chemical compound, 3-propiony1salicylic acidv This compound has been mentioned in US. Pat. No. 2,921,070, but without any characteristic allowing it to be identified, and it was later recognized that the method described in that patent for preparing this product did not produce the desired 3-propionylsalicylic acid, but S-propionylsalicylic acid.

In accordance with this invention, the starting compound is 2-hydroxy-3-allylpropiophenone, a compound already described (Takahoshi et alia, J. Pharm. Soc. Japan, 74, 48, l954). This compound is first isomerised into 2'hydroxy-3propenylpropiophenone with an alkali, By oxidizing 2-hydroxy-3-propenylpropiophenone with ozone at about C in a medium which consists of a mixture of formic acid and acetic acid, 3-propionylsalicylic aldehyde is obtained. Finally, the latter compound is subjected to.an alkaline ;fusion to oxidize it into the desired 3-propionylsalicylic acid.

Also in accordance with the invention, 3-propiony'lsalicylic acid prepared according to the above method is used for the preparation of known derivatives, the lower alkyl esters of 3-methylflavone-8-carboxylic acid. For this purpose, 3-propionyl-salicylic acid is converted to a lower alkyl ester, e.g., methyl or propylester, preferably ethyl ester, then, the ester is cyclised in the presence of sodium benzoate andbenzoyl chloride at a temperature of about l80'l90C. The lower alkyl ester of 3-methylflavone S-carboxylic acid is thu's-obtained, from which the acid can easily be freed by alkaline saponification. The amount of alkali used for this saponification must not exceed the stoechiometric amount, otherwise the gamma pyrone ring might be broken downl 3-methylflavone-8-carboxylic acid and its lower alkyl esters are useful starting materials for the preparation of esters of this acid with aminoalcohols. These basic esters are known therapeuticalj agents, particularly B-piperidinoethyl 3-methylflavone-S-carboxylate, B-morpholinoethyl 3-methylfalvone 8-carboxylate, B-diethylaminoethyl -3-methylflavone-8-carboxylate, ,8-di-n-pro pylaminoethyl v 3-methylflavone-8- carboxylate, and ,B-di-isopropylaminoethyl 3 methylflavone-8-carboxylate.

The fl-piperidinoethyl ester of 3-methylflavone-8 -carboxylic acid, as well as other esters of the same acid with different aminoalcohols. may be prepared by direct esterification, preferably transesterification, by reacting an excess of the corresponding aminoalcohol with the ethyl ester of 3-methylflavone-8-carboxylic acid in the presence of a catalyst such as metallic sodium.

. For the preparation of injectable solutions of these basic esters, they should be converted into acid addition salts which are sufficiently water soluble andpharmaceutically acceptable. Whereas ,B-piperidinoethyl 3-methylflavone-8-carboxylate hydrochloride and tartrate are not very soluble in water and therefore cannot be used for preparing injectable solutions which are sufficiently concentrated to have the required therapeutic efficiency, other acid addition salts of the above mentioned ester are sufficiently soluble, for instance the phosphate and succinate. I

The following examples illustrate the invention.

EXAMPLE -l 3-propionylsalicylaldehyde 24.4 g of 2-hydroxy-3-propenylpropiophenone, suspended in a mixture of 60 ml of acetic acid and 30 ml of formic acid, are ozonised by passing a stream of oxygen l5 litres/hour) containing 7% of 0 through the suspension. The operation is carried out for 4 /2 hours at 0C.

When the ozonisation is completed, a stream of pure oxygen is passed during -l5- minutes' through the solution which-is heated to 40'45C. After main-taining the mixture at 4045C for' 15 minutes more, it is slowly poured into water with. stirring. A semisolid product separates, which is washed twice'by decantation in water; it is taken up with ether land the ether solution is washed with a solution of sodium'bicarbonate (by acidify'ing this solution withHCl, 1 .3 g of 3-propionylsalicy lic acid are precipitated), then the ether solution is washed with water and is dried over anhydrous sodium sulfate. v v

- The solvent is evaporated. and the residue is vacuum distilled. 14 g of the desired productwhich boils at l30-l 35C (2.5 mm Hg) and which solidifies on cooling are thus obtained. This product be used directly for the next step. Total yield 67.2%. The pure product, which melts at 57,'5.9C', is obtained by crystallization in ligroin.

, The 2-hydroxy-3-propenylpropiophenone starting compound may bejprepared by isomerisation of 2- hydroxy-3-allylpropiophenone, as followsz,

To g of 2-hydroxy-3-allylpropiophenone, dissolved in 156 ml of diethyleneg'lycol, are added, with stirring, 49 g of potassiu'm"hydroxyde pellets, the solu tion is refluxed for 8 hours and then cooled to 20C. 200 ml of water and 200 ml of chloroform are added to the reaction mixture, and it is cautiously neutralised to pH 6-7 with concentrated hydrochlorid acid. The mixture is stirred, the lower chloroform layer is collected and the aqueous phase is extracted once more with 70 ml of chloroform. The solvent is evaporated from the combined chloroform extracts and the residue is crystallized in methanol. 61g ofthe desired product.

which melts at 8285C are. obtained.

EXAMPLE 2 I 3-propionylsalicylic acid A well-triturated mixture of 9 g of 3-propionylsalicylic aldehyde and 10 g of potassium hydroxyde is slowly heated. Already at about 1 10C, a fairly rapid evolution of hydrogen is observed. After having gradually heated the mixture for half an hour so as to obtain finally a maximum temperature of 200C, the mass is allowed to cool completely andtaken up with boiling water. The

solution is cooled, filtered if necessary and slowly aciditied with hydrochloric acid, and the precipitate is collected and washed with a little cold water. After crystallization in dilute alcohol, 8.3 g of 3-propionylsalicylic acid which melts at 1241 25C are obtained;

Ethyl 3-propionylsalicylate I v 6 g of 3-propionylsalicylic acid are dissolved in 30 ml of absolute ethyl alcohol and a little concentrated sulfuric acid is added. The solution is refluxed for hours, it is allowed to cool, diluted with water and extracted with ether. The ether extracts are washed with a 5% solution of sodium bicarbonate,- then with water, and then dried over anhydrous sodium sulfate. After evaporating the solvent, 6.0 g of ethyl 3-propionylsalicylate remain, which may be used directly forthe next step: melting point 4849C.

Analysis: For C H O, ("/1 H71 Calculated: 64.85 6.35

Found: 64.96 6.62

EXAMPLE 4 Ethyl 3-methylflavonev8-carboxylate A mixture of 3.4 g of ethyl 3-propionylsalieylate, 19 g of sodium benzoate and 16 g of benzoyl chloride are heated to 180190C for 8 hours. the reaction mixture is treated with an excess ofa chilled 4% solution of Na- CO with vigorous stirring which is continued until a solid product is formed which is washed with water. After crystallization" in ligroin, 4.1 g of ethyl 3-methylflavone-X-carboxylate which melts at 9799C are obtained. 1

Analysis: For C HmO,

C91 H71 Calculated: 74.01 5.23 Found: 73.80 4.97 7

EXAMPLE 5 3-methylflavone-8-carboxylic acid EXAMPLE 6 3-methylflavone 8-carboxylic'acid chloride A mixture of 56 g of 3-methylflavone-8-carboxylic acid and 53 g of thionyl chloride in 500 ml of benzene is refluxed for 3 hours. Then the benzene is vacuum distilled, further benzene is added to the flask and the last traces of thionyl chloride are removed by another distill'ati'on. The desired chloride is thus obtained in a substantially theoretical amount, and it is used directly for the following condensation.

EXAMPLE 7 8-piperidinoethyl' 3methylflavone-8-carboxylate hydrochloride 7 .50 g of 3-methylflavone8-carboxylic acid chloride in 650 ml of. benzene are heated to 50C, and 22 g of ,B-piperidinoethanol are added thereto. The mixture is kept boiling for 3 hours, and then it is cooled and filtered. The productcollected on the filter is crystallized in 95% ethyl, alcohol, and 61 g of a product melting at 230233C are obtained.

EXAMPLE 8 ,8-piper ridinoethyl 3-methylflavone-8-carboxylate hydrochloride 7.29 g of 3-methylflavone-S-carboxylic acid'and 4.79 g of ,B-piper-idinoethyl" chloride hydrochloride are suspended in 100 ml of-isopropanol and, with stirring, 24.9 ml of 2.09 N rnetha'nolic KOH are added to the suspension. The mixture is refluxed for 30 minutes, it is cooled and the solvent is evaporated at the water-bath temperature at a pressure of 15-20 mm of Hg. The residue is taken up with benzene and some 5% Na CO solution, and the organic phase is separated. The'organic phase iswashed with water, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. Thebase is taken up with ether and, after a treatment with ethanolic hydrochloric acid, the hydrochloride is obtained which, after crystallization in methanol, melts at 230-233C.

Analysis: For C H NO HCI C7: H71

Calculated: I 67.62 6.13 3.27 8.30 Found: 67.54 6.21 3.22 8.27

' EXAMPLE 9 B-piperidinoethyl 3-methylflavone8carboxylate 100 g of sodium are dissolved in 50 ml of piperidinoethanol and 6 g of ethyl 3-methylflavone-8-carboxylate are added to the solution. The mixture is left at room temperature for 24 hours, then it is heated under nitrogen at 90100C and the excess of aminoalcohol and the ethanol formed during the reaction are allowed to distil slowly over approximately 2 hours at a pressure of 7-8 mm of Hg. The oily residue is dissolved in cold 0.1 N sulfuric acid. The acidic solution is filtered (with charcoal), it is cooled in ice, and graduallytreated with an aqueous solution of 5% sodium carbonate, with stirring, until complete precipitation of the base which is recovered. washed and dried. Yield: 6.2 g; melting'at 85C. After crystallization in cyclohexane, the melting point is raised to 86C.

Analysis: For C ,H NO,

EXAMPLE l0 B-piperidinoethyl 3-methylflavone-8-carboxylate succinate A solution of 1.95 g of B-piperidinoethyl Calculated: 65.99 6.13 2.75

Found: 65.94 6.24 2.68

EXAMPLE 1 l Mono-B-piperidinoethyl 3-methylflavone-8carboxylate orthophosphate 0.01 mole of B-piperidinoethyl 3methylflavone-8- carboxylate are dissolved in volumes of acetone at room temperature. With vigorous stirring 0.01 mole of H PO is slowly added as an 85% solution. The desired salt precipitates immediately in a sticky form, and with vigorous stirring, it is fairly quickly converted to a crystalline form. It is cooled to 0C to complete the precipitation, filtered off, washed with a little acetone, and vacuum-dried. This crude product is crystallized once in absolute methanol and a white crystalline product melting at l94l95C is obtained. Yield: 3.0 g. The solubility of this salt in water at room temperature is 1 claim:

l. A method for preparing esters of 3-methylflavone- 8-carboxylic acid with aminoalcohols. wherein 2- hydroxy-3-allylpropiophenone is subjected to an isomerisation treatment comprising dissolving it in a solvent and refluxing the solution under alkaline conditions to convert it to 2-hydroxy-3- propenylpropiophenone. the latter is oxidized with ozone at a temperature of about 0C in a reaction medium which consists of a mixture of formic acid and acetic acid to produce 3propionylsalicylic aldehyde, then the latter compound is subjected to an alkaline fusion to oxidize it to 3-propionylsalicylic acid. the latter is esterified with a lower alkanol, then the 3-propionyl salicylic acid lower alkyl ester is reacted with sodium benzoate and benzoyl chloride at a temperature of about -l90C to produce a 3-methylflavone-8- carboxylic acid lower alkyl ester and the ester is transesterified with an aminoalcohol or. if desired. the lower alkyl ester is hydrolized to produce free 3-methylflavone-8-carboxylic acid and the said acid is esterified with an aminoalcohol. said aminoalcohol being selected from the group consisting of ,B-piperidinoethanol, B-morpholinoethanol, ,B-diethyl aminoethanol, Bdi-n-propylaminoethanol and ,B-diisopropylaminoethanol.

2. A method according to claim 1, for preparing the B-piperidinoethyl ester of 3-methylflavone-8- carboxylic acid, wherein the aminoalcohol used is ,B-piperidinoethanol.

3. A method according to claim 1 wherein the solvent employed in the isomerisation treatment is diethyleneglycol and wherein potassium hydroxide is added to obtain the alkaline condition.

4. A method according to claim 3, wherein the solution is refluxed for 8 hours during the isomerisation treatment and upon cooling the mixture is neutralized to a pH of 67 with concentrated hydrochloric acid.

l =l i UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,892,759

DATED July 1, 1975 V TOR( 1 Enrico SIANESI It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below;

Please correct the name of the assignee to read -RECORDATI S.A. CHEMICAL AND PHARMACEUTICAL COMPANY";

II II I Column 3, llne 5, :Lnstead of For C H O please lnsert -For C H O Column 4, line 7, instead of "-piperidinoethyl...",

please insert -/piperidinoethyl. and

line 19, instead of "fl-piperridinoethyl", please insert -/@-piperidinoethyl-.

Signed and Scaled this sixteenth -D a 0f December 19 75 [SEAL] A ties r:

RUTH C. MASON C. MARSHALL DANN A lesling Office Commissioner oj'Parents and Trademarks 

1. A METHOD FOR PREPARING ESTERS OF 3-METHYLFLAVONE-8-CARBOXYLIC ACID WITH AMINOALCOHOLS, WHEREIN 2-HYDROXY-3-ALLYLPROPIOPHENONE IS SUBJECTED TO AN ISOMERISATION TREATMENT COMPRISING DISSOLVING IN A SOLVENT AND REFLUXING THE SOLUTION UNDER ALKALINE CONDITIONS TO CONVERT IT TO 2-HYDROXY-3PROPENYLPROPIOPHENONE, THE LATTER IS OXIDIZED WITH OZONE AT A TEMPERATURE OF ABOUT 0*C IN A REACTION MEDIUM WHICH CONSISTS OF A MIXTURE OF FORMIC ACID AND ACETIC TO PRODUCE 3-PROPIONYLSALICYLIC ALDEHYDE, THEN THE LATTER COMPOUND IS SUBJECTED TO AN ALKALINE FUSION TO OXIDIZE IT TO 3-PROPIONYSALICYLIC ACID, THE LATTER IS ESTERIFIED WITH A LOWER ALKANOL, THEN THE 3PROPIONYLSALICYLIC ACID LOWER ALKYL ESTER IS REACTED WITH SODIUM BENZOATE AND BENZOYL CHLORIDE AT A TEMPERATURE OF ABOUT 180* -190*C TO PRODUCE A 3-METHYFLAVONR-8-CARBOXYLIC ACID LOWER ALKYL ESTER AND THE ESTER IS TRANSESTERIFIED WITH AN AMINOALCOHOL OR, IF DESIRED, THE LOWER ALKYL ESTER IS HYDROLIZED TO PRODUCE FREE 3-METHYFLAVONE-8-CARBOXYLIC ACID AND THE SAID ACID IS ESTERIFIED WITH AN AMINOALCOHOL, SAID AMINOALCOHOL BEING SELECTED FROM THE GROUP CONSISTING OF B-PIPERIDINOETHANOL, B-MORPHOLINOETHANOL, B-DIETHYLAMINOETHANOL, B-DI-NPROPYLAMINOETHANOL AND B-DI-ISOPROPYLAMINOETHANOL.
 2. A method according to claim 1, for preparing the Beta -piperidinoethyl ester of 3-methylflavone-8-carboxylic acid, wherein the aminoalcohol used is Beta -piperidinoethanol.
 3. A method according to claim 1 wherein the solvent employed in the isomerisation treatment is diethyleneglycol and wherein potassium hydroxide is added to obtain the alkaline condition.
 4. A method according to claim 3, wherein the solution is refluxed for 8 hours during the isomerisation treatment and upon cooling the mixture is neutralized to a pH of 6-7 with concentrated hydrochloric acid. 